Editors' ChoiceCancer

An apple a day may not keep the doctor away, if you have AML

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Science Translational Medicine  02 Nov 2016:
Vol. 8, Issue 363, pp. 363ec174
DOI: 10.1126/scitranslmed.aaj2089

Increased aerobic glycolysis with lactate production (the Warburg effect) is a common feature of cancer. Because most normal cells do not rely on the Warburg effect, aberrant metabolic pathways may represent a therapeutic vulnerability in the treatment of cancer. Aberrant metabolism has also been demonstrated to have a role in the pathogenesis and progression of acute myeloid leukemia (AML).

Now, Chen and colleagues advance the field further by building on previous findings concerning high glycolytic and tricarboxylic acid (TCA) cycle activity in AML. The leukemic bone marrow environment is low in glucose, and therefore the researchers postulated that an alternative source must fuel glycolytic activity in AML. Because fructose is the second most abundant blood sugar in humans, they examined the role of fructose and of the fructose transporter GLUT5 (encoded by the gene SLC2A5). The authors found that GLUT5 or SLC2A5 were indeed statistically significantly more highly expressed in leukemic blasts than in normal hematopoietic cells. Then, they carefully measured serum fructose in AML patients with active disease compared with normal controls or AML patients in remission, finding that fructose concentrations were lower in active AML, suggesting active consumption of this fuel source. Furthermore, in patients showing high rates of fructose utilization, there was an increased risk of treatment failure (defined as lower rates of complete remission), although the authors did not find differences in event-free or overall survival. Mechanistic studies then showed that knockdown of SLC2A5 in AML cell lines decreased cell proliferation, whereas overexpression of SLC2A5 increased fructose consumption in association with features of malignancy, such as increased proliferation, colony growth, migration, and invasiveness. Last, blockade of fructose uptake with the fructose analog 2,5-AM ameliorated the malignant phenotype in vitro and resulted in modest reductions in leukemic burden, along with enhancement of survival in mice bearing AML.

These findings continue to explore the recent theme of metabolic vulnerability in cancer. Although the mechanistic studies are compelling, the relatively modest effect on AML progression in the tumor-bearing mouse model suggests that fructose metabolism may be an epiphenomenon rather than a true driver of pathogenicity in AML. Therefore, it is likely too early to disregard the old adage "an apple a day keeps the doctor away."

W.-L. Chen et al., Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer Cell 10.1016/j.ccell.2016.09.006 (2016). [Abstract]

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